Therapy of cancer by cytokines mediated by gene therapy approach. Cell Res

Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China.
Cell Research (Impact Factor: 12.41). 03/2006; 16(2):182-8. DOI: 10.1038/
Source: PubMed


Gene therapy offers a new approach for treatment of cancer. Transfer of genes encoding immunostimulatory cytokines has been used with remarkable success to eliminate cancer in animals. However, clinical trials in patients with this strategy had limited efficacy. Therefore, improvement of gene transfer vector system is necessary. A hybrid viral vector, consisting of SFV replicon with either murine IL-12 or reporter LacZ gene, was constructed. This hybrid vector showed specificity and high level of expression in HCC both in vitro and in vivo. In a rat orthotropic liver tumor model, treatment of established tumors by the hybrid vector with mIL-12 gene resulted in a strong anti-tumor activity without accompanying toxicity. Subsequently, a helper-dependent adenovirus vectors containing a mifepristone (RU486) inducible system was constructed for controlled and liver-specific expression of human interleukin 12 (hIL-12) (HD-Ad/RUhIL-12) and mouse IL-12 (mIL-12) (HD-Ad/RUmIL-12). Data showed that high and sustained serum levels of hIL-12 could be attained by continuing administration of RU486 every 12 or 24 h. Repetitive induction of hIL-12 could be obtained over, at least, a period of 48 weeks after a single injection of HD-Ad/RUhIL-12. Treatment of liver metastases with of HD-Ad/RUmIL-12 plus RU846 resulted in complete tumor regression in all animals. Then, different cytokine genes were inserted into conditional replicative adenoviruses vectors (also called oncolytic adenovirus). Replication of adenovirus in tumor cells would kill tumor cells and release viruses, which infect surrounding tumor cells. The combination of cytopathic effect by oncolytic adenovirus and biological effect of transgene would exert strong antitumor activity. These new types of vectors may provide a potent and safe tool for cancer gene therapy.

10 Reads
  • Source
    • "For safety, oncolytic viral replication must be controlled strictly within tumor cells. Thus, the different types of viruses have been genetically modified, including vaccinia, adenovirus, herpes simplex virus type I, reovirus and Newcastle disease virus [16], [17], [18], [19], [20]. One of the common strategies used to design oncolytic adenoviruses is to modify adenoviral E1A protein. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Both adoptive immunotherapy and gene therapy hold a great promise for treatment of malignancies. However, these strategies exhibit limited anti-tumor activity, when they are used alone. In this study, we explore whether combination of cytokine-induced killer (CIK) adoptive immunotherapy with oncolytic adenovirus-mediated transfer of human interleukin-12 (hIL-12) gene induce the enhanced antitumor potency. Our results showed that oncolytic adenovirus carrying hIL-12 (AdCN205-IL12) could produce high levels of hIL-12 in liver cancer cells, as compared with replication-defective adenovirus expressing hIL-12 (Ad-IL12). AdCN205-IL12 could specifically induce cytotoxocity to liver cancer cells. Combination of CIK cells with AdCN205-IL12 could induce higher antitumor activity to liver cancer cells in vitro than that induced by either CIK or AdCN205-IL12 alone, or combination of CIK and control vector AdCN205-GFP. Furthermore, treatment of the established liver tumors with the combined therapy of CIK cells and AdCN205-IL12 resulted in tumor regression and long-term survival. High level expression of hIL-12 in tumor tissues could increase traffic of CIK cells to tumor tissues and enhance their antitumor activities. Our study provides a novel strategy for the therapy of cancer by the combination of CIK adoptive immunotherapy with oncolytic adenovirus-mediated transfer of immune stimulatory molecule hIL-12.
    PLoS ONE 09/2012; 7(9):e44802. DOI:10.1371/journal.pone.0044802 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The syntheses and characterization of mesoporous silica and functionalized mesoporous silica obtained by neutral polyoxiethylene surfactants are reported. Syntheses were carried out according to a new interfacial procedure based on a slow-rate not-catalyzed tetraethylortosilicate hydrolysis aimed to tailor the particle size of the final product. Synthesis systems are consituted by a two-level byphasic emulsion and mesoporous silica particles grow at the interface of the organic (upper) and the inorganic (lower) regions. The newly-formed particles migrate because of the gravity force to the bottom of the synthesis vessel, far from the upper silica-feeding solution. Typical particle size is at the nanometer scale. Solids with high thermal stability, high pore volume and specific surface SBET up to 900 m2/g are obtained at room temperature starting from synthesis not including a mineralizing agent such as H+, OH− or F− ions.
    Studies in surface science and catalysis 01/2005; 158:557-564. DOI:10.1016/S0167-2991(05)80385-4
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The constitutive activation of signal transducer and activator of transcription 3 (STAT3) participates in carcinogenesis through up-regulation of genes encoding apoptosis inhibitors and cell cycle regulators, such as Bcl-xL, cyclins D1 and D2, and c-myc. Suppressor of cytokine signaling 3 (SOCS3) is one of the negative regulators of cytokine signaling and is frequently silenced in diverse cancers. In this study, we explored whether restoration of SOCS3 by oncolytic adenoviral vectors could inhibit the constitutive activation of the Janus kinase/STAT pathway and suppress tumor growth. Our data showed that SOCS3 was down-expressed in all liver tumor cell lines. The incorporation of SOCS3 or SOCS3 fused with cell-penetrating peptides (cpp-SOCS3) did not alter adenoviral replication selectively in liver tumor cells. The infection of cells with adenovirus CN305 (AdCN305)-SOCS3 and AdCN305-cpp-SOCS3 resulted in dramatic cytotoxicity in liver tumor cells. However, no cytotoxic effect was observed in normal cells infected with these vectors. Infection of liver tumor cells with AdCN305-SOCS3 and AdCN305-cpp-SOCS3 resulted in nearly complete inhibition of STAT3 phosphorylation and down-regulation of cyclin D1 and Bcl-xL. Treatment of the established tumor by AdCN305-SOCS3 and AdCN305-cpp-SOCS3 caused significant suppression of tumor growth. The suppression of tumor growth was due to the inhibition of STAT3 phosphorylation and induction of tumor cell death. Conclusion: This study suggests that transfer of SOCS3 by an oncolytic adenovirus represents a potent approach for cancer therapy.
    Hepatology 10/2007; 47(1):105-12. DOI:10.1002/hep.21951 · 11.06 Impact Factor
Show more


10 Reads
Available from